Claims
- 1. A guanidinobenzoic ester compound of the formula: ##STR26## wherein X represents a group of the formula: ##STR27## in which Y is a group of the formula: --(CH.sub.2).sub.m --, m being an integer of 3, ##STR28## and n represents an integer of 1 to 5, and pharmacologically acceptable salt thereof.
- 2. Guanidinobenzoic ester compounds according to claim 1 wherein X represents a group of the formula: ##STR29## in which Y is a group of the formula: --(CH.sub.2).sub.m --, m being an integer of 3, ##STR30##
- 3. Guanidinobenzoic ester compounds and pharmacologically acceptable salts of them according to claim 1, wherein X represents a group of the formula: ##STR31## in which Y is a group of the formula: --(CH.sub.2).sub.m --, m being an integer of 3, ##STR32##
- 4. Guanidinobenzoic ester compounds and pharmacologically acceptable salts of them according to claim 1, wherein n is 2 to 5.
- 5. Guanidinobenzoic ester compounds and pharmacologically allowable salts of them according to claim 1, wherein n represents 2 to 5 and X represents a group of the formula: ##STR33## in which Y is a group of the formula: --(CH.sub.2).sub.m --, m being an integer of 3, ##STR34##
- 6. Guanidinobenzoic ester compounds and pharmacologically allowable salts of them according to claim 1, wherein n represents an integer of 2.
- 7. Guanidinobenzoic ester compounds and pharmacologically allowable salts of them according to claim 1, wherein n represents an integer of 2 and X represents a group of the formula: ##STR35## in which Y is a group of the formula: --(CH.sub.2).sub.m --, m being an integer of 3, ##STR36##
- 8. Guanidinobenzoic ester compounds and pharmacologically allowable salts of them according to claim 1, wherein n represents an integer of 2 to 5 and X represents a group of the formula: ##STR37## m being an integer of 3.
- 9. A guanidinobenzoic ester derivative or its pharmacologically allowable salt according to claim 1, wherien the compound is 4-(20phthalimidoethylthio)phenyl 4-guanidinobenzoate.
- 10. A guanidinobenzoic ester derivative or its pharmacologically allowable salt according to claim 1, wherein the compound is 4-[2-(cis-1,2-cyclohexanedicarboxyimido)ethylthio]phenyl 4-guanidinobenzoate.
- 11. A guanidinobenzoic ester derivative or its pharmacologically allowable salt according to claim 1, wherein the compound is 4-[2-(5,5-dimethyl-2,40dioxooxazolidin-3-yl)ethylthio]phenyl 4-guanidinobenzoate.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 60-293268 |
Dec 1985 |
JPX |
|
STATEMENT OF PRIOR ART
This is a division of Ser. No. 07/225 278, filed July 28, 1988, now U.S. Pat. No. 4,948,508 which is a division of Ser. No. 06/946 458, filed Dec. 24, 1986, now U.S. Pat. No. 4,801,603.
The invention relates to a guanidinobenzoic ester derivative, a process for preparing the compound, a pharmaceutical composition containing the same, and a method for treating a special disease with the compound.
Pancreatitis is clinically divided into acute pancreatitis and chronic pancreatitis. When the causes or factors of acute pancreatitis are removed, the pancreas recovers from the illness into a normal state both clinically and biologically. On the other hand even when the causes or factors thereof of chronic pancreatitis are eliminated, the histological and functional disorders still remain. Though the causes of pancreatitis have not fully been understood, the number of patients of alcoholic pancreatitis is the largest followed by those of ill-defined (idiopathic) pancreatitis and cholelithiasic pancreatitis in Japan.
The process from the initial stage to the crisis stage of pancreatitis is complicated and has not been fully understood. Antienzymatic therapty is employed frequently as a pharmacotherapy at present and the further developmetn of a pancreatic enzyme inhibitor having a higher safety and better effects is demanded.
An object of the present invention is to provide new guanidinobenzoic ester derivatives. Another object of the invention is to provide a process for producing said guanidinobenzoic ester derivatives. Still another object of the invention is to provide medicines containing as an active ingredient said guanidinobenzoic ester derivative.
The intended compounds of the present invention are guanidinobenzoic ester derivatives of the following general formula (I) and pharmacologically allowable salts thereof: ##STR4## wherein X represents a group of the formula: ##STR5## in which Y is a group of the formula: --(CH.sub.2).sub.m --, m being an integer of 2 or 3, ##STR6## or a group of the formula:
The lower alkyl groups in the above definition of R are straight chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups.
Examples of the pharmacologically acceptable salts include inorganic acid addition salts such as hydrochlorides, sulfates, hydrobromides, perchlorates and hydriodides and organic acid addition salts such as oxalates, maleates, fumarates, succinates and methanesulfonates.
The compounds (I) and pharmacologically allowable salts of them according to the present invention have a strong inhibiting effect on enzymes such as trypsin, plasmin and thrombin and, therefore, they can be used as trypsin inhibitors effective for the treatment of pancreatitis, plasmin inhibitors effective for the treatment of hemorrhagic diseases and thrombin inhibitors effective for the treatment of thrombosis.
The compounds (I) of the present invention can be produced be various processes. Typical examples of them will now be described.
The intended compounds of the present invention can be obtained by esterifying a guanidinobenzoic acid of the following formula (II): ##STR7## with a compound of the general formula (III): ##STR8## wherein X and n are as defined above, in an ordinary manner. In the most typical process, guanidinobenzoic acid of the above formula (II) or its reactive derivative is esterified with the compound of the above general formula (III). More particularly, the intended compound (I) of the present invention can be obtained by reacting a halide of guanidinobenzoic acid (II), i.e. a compound of the following formula (II'), obtained easily by, for example, heating the compound (II) together with thionyl chloride: ##STR9## wherein Hal represents a halogen atom such as chlorine or bromine, with the compound (III) in the presence of an acid-binding agent such as pyridine or triethylamine. Examples of organic solvents usable in this process include tetrahydrofuran, ether, benzene, toluene, dimethylformamide, pyridine and dimethyl sulfoxide. Among them, pyridine is the most preferred. When using an organic solvent other than pyridine, an organic amine such as triethylamine, tributylamine, dimethylamine or pyridine or an inorganic base such as calcium carbonate, sodium carbonate or sodium hydroxide may be used as the acid-binding agent.
In another process, guanidinobenzoic acid of the above formula (II) is directly condensed with a compound of the formula (III) in the presence of a dehydrating agent such as DCC (1,3-dicyclohexylcarbodiimide).
When X in the above formula (I) represents --OH in both of the above-mentioned processes, a compound of the general formula (III'): ##STR10## is used as the compound (III). In such a case, the hydroxyl group bonded with the alkylene is protected with a protective group used in an ordinary chemical reaction in the course of the reaction and the protective group is removed from the hydroxyl group after completion of the reaction. Typical examples of the protective groups include benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, triphenylmethyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, tetrahydropyranyl and tetrahydrothiopyranyl groups.
The compounds (I) obtained by the above-mentioned processes can be suitably converted into pharmacologically allowable acid addition salts by ordinary process.
In one embodiment, the obtained compound (I) is treated with an aqueous sodium hydrocarbonate solution to form a carbonate and, if necessary, the carbonate can be converted easily into a salt with an inorganic acid such as hydrochloric, sulfuric, phosphoric, hydrobromic or nitric acid or an organic acid such as formic, acetic, lactic, tartaric, oxalic, citric, succinic, fumaric, maleic, methanesulfonic, benzenesulfonic or toluenesulfonic acid.
The starting compounds (III) used in the above-mentioned process can be prepared by, for example, the following process:
(i) when X in the formula (I) represents a group of the formula: ##STR11## in which Y is as defined above, and n represents an integer of 2 to 5: ##STR12## in which Hal is a halogen atom and n and Y are as defined above.
A 1, n-dihalogenoalkane (IV) in which the halogen is preferably bromine or chlorine is condensed with an imide compound of the formula (V) in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide to obtain a compound of the formula (VI). This reaction is carried out in an organic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, propanel, isopropanel, butanol, and dimethylformamide (DMF) of dimethyl sulfoxide (DMSO). ##STR13## in which n and Y are as difined above.
The compound (VI) obtained in step 1 is condensed with 4-hydroxythiophenol of the formula (VII) in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydrocarbonate, sodium hydroxide or potassium hydroxide to obtain a compound (III"). This reaction is carried out in an organic solvent such as methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).
(ii) To obtain a compound of the formula (I) wherein X represents a group of the formula:
(iii) When n in the formula (I) is 1, the following process can be employed: ##STR15##
Typical examples of the compounds of the present invention will be given below to facilitate understanding of the present invention, which by no means limit the invention:
The following experiments will prove the pharmacological effects of the compounds of the present invention.
The effects of typical compounds of the present invention in inhibiting trypsin, plasmin and thrombin in vitro were examined. The trypsin-inhibiting effect was represented in terms of a molar concentration of the compound which inhibits the activity of 0.5 .mu.g/ml of trypsin to hydrolyze benzoyl-D,L-arginine-p-nitroanilide hydrochloride by 50% at 25.degree. C. In the determination of the plasmin- and thrombin-inhibiting effects, 50% inhibitory concentrations were determined by using H-D-Val-Leu-L-Lys-p-nitroanilide dihydrochloride and H-D-Phe-L-pipecolyl-L-Arg-p-nitroanilide dihydrochloride, respectively, as the substrate.
The results are shown in Table 1
It is apparent from the results of the above experiments that the compounds of the present invention have a strong inhibitory effect against enzymes such as trypsin, plasmin and thrombin.
The compounds A to I used in the above experiments were subjected to acute toxicity tests by administration to ICR mice by intravenous injection. These compounds had an LD.sub.50 in the range of 50 to 200 mg/kg.
Thus, the compounds of the present invention have excellent inhibiting effects on enzymes such as trypsin, plasmin and thrombin and, therefore, they can be used for the treatment of chronic and acute pancreatitis by virtue of their trypsin-inhibiting activity or for the treatment of hemorrhagic diseases and thrombosis by virtue of their plasmin- and thrombin-inhibiting activities.
The compounds of the present invention are given in an amount of about 5 to 1,000 mg/day, preferably about 10 to 500 mg/day, to adult patients at least once a day either orally or parenterally, though the dose is not particularly limited, since it varies depending on the kind of diseases, extent of symptoms, age of the patient, physical conditions, body weight, kind of concomitant treatments, if any, frequency of the treatment and intended effects. Particularly in the treatment of pancreatitis, the dose is within the above-mentioned range, preferably about 10 to 500 mg/day and more preferably about 30 to 300 mg/day, for adults.
The dosage forms of the compounds of the present invention include, for example, powders, fine granules, granules, tablets, capsules, suppositories and injections. These pharmaceutical preparations are produced by an ordinary process by using an ordinary pharmaceutical carrier.
Namely, in the production of an oral solid preparation, an excipient and, if necessary, a binder, disintegrator, lubricant, colorant, corrigent, etc. are added to the active ingredient and the mixture is shaped into tablets, coated tablets, granules, powders or capsules.
Examples of the excipients include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide. Examples of the binders include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia gum, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone. Examples of the disintegrators include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin and pectin. Examples of the lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. The colorants are those permitted to be added to medicines. Examples of the corrigents include cocoa powder, menthol, aromatic powder, peppermint oil, borneol and cinnamon powder. These tablets and granules may be coated suitably with sugar, gelatin, etc., if necessary.
In the preparation of the injection, a pH-controlling agent, buffering agent, stabilizer, solubilizer, etc. are added, if necessary, to the active ingredient to form an intravenous injection in an ordinary manner.
Non-Patent Literature Citations (1)
| Entry |
| Choay et al., Chemical Abstracts, vol. 95, 1981 p. 639, :132533x. |
Divisions (2)
|
Number |
Date |
Country |
| Parent |
225278 |
Jul 1988 |
|
| Parent |
946458 |
Dec 1986 |
|
Patent Grant
5075335
